Matt Hoffman, Managing Editor for NeurologyLive, has covered medical news for MJH Life Sciences, NeurologyLive’s parent company, since 2017. He hosts the NeurologyLive 

 show, Second Opinion. Follow him on Twitter 

Matt Hoffman

Since its approval on June 7, 2021, aducanumab (Aduhelm; Biogen/Eisai) has maintained its place as a major hot topic in the conversations among those in the field of Alzheimer disease (AD) and dementia. Particularly, those conversations have in part focused on which individuals are best suited for treatment with the antiamyloid infusion therapy.

Shortly after its approval, the FDA announced an update to the drug’s label, stating that treatment with aducanumab should be initiated in patients with mild cognitive impairment or mild dementia stages of the disease, the population in which the treatment was initiated in clinical trials. It continues to state that there are no safety or efficacy data on initiating treatment at earlier or later stages of the disease than were studied. Despite this, there remains a need to educate physicians on the identification of these patients and the complexities of the therapy.

2021 Alzheimer Association International Conference

 (AAIC), July 26-30, a number of physicians presented appropriate use criteria for aducanumab in order to clarify some of these lingering questions, which were published in 

The Journal of Prevention of Alzheimer's Disease

 prior to the meeting. Among them was Jeffrey L. Cummings, MD, ScD, professor of brain science, and director, Chambers-Grundy Center for Transformative Neuroscience, University of Nevada–Las Vegas.

: What are the key takeaways from the presentation of these criteria?

 People have wondered how these criteria came about and why we would provide appropriate use criteria for a drug that has just been approved. The group that I was working with looked at the package insert that was approved on June 7 and saw that there was not sufficient detail for clinicians who were unfamiliar with aducanumab to actually know how to take the first, second, and third steps to initiate an aducanumab treatment program. So, we put together an appropriate use committee that has produced these appropriate use recommendations.

They deal very seriously with safety, how to manage the ARIA [amyloid-related imaging abnormalities] and the safety of aducanumab, and how to choose the patient for aducanumab—because we want to keep those patients very close to the trial patients in terms of their characteristics—and then how to talk with the patients. This is a complicated drug. The patient has to commit themselves to monthly infusions, they have to commit themselves to frequent MRI scanning in the first year, they have to know that ARIA occurs and that it can be a symptomatic outcome of the treatment with aducanumab. The shared decision-making between the clinician and the patient is extremely important for this particular agent, and we emphasize that a lot in terms of the appropriate use recommendations.

Do you foresee a widespread physician education effort happening around the use of this drug?

I think the education of the physician is going to be a tremendously important part of this rollout in order to make the use of aducanumab both proper and safe. What we've heard already is that our appropriate use recommendations are being taken by the pharmacy committees of hospitals to help guide how their programs should be constructed. Once the programs have a kind of infrastructure established, then the physician education can begin to provide the know-how about moving the drug out, talking with patients about it, administering it, and monitoring it. I see this as a stepwise process, beginning with the pharmacy committees and then eventually going out to both patient education and physician education.

Aducanumab Phase 4 Real-World Observational Study Announced

Are there any lingering questions about the therapy that you’ve gotten?

Well, I rarely deal with the price or cost of drugs, but in this case, of course, that is a major question. Will Medicare provide coverage for aducanumab and other monoclonal antibodies that we think will be coming out from other companies? That answer is currently unclear. CMS has given it a lot of thought at this point to decide how coverage should occur and how they would decide to cover it. That's a critical issue, and it is critical for doctors and healthcare systems. That will have to be resolved before we'll be able to have complete use of aducanumab for the appropriate patients.

Outside of aducanumab’s entrance into the clinic, what's the big item that you're keeping your eyes on in AD?

The blood tests for Alzheimer disease are just making so much great progress and are going to be so informative in a whole variety of ways. Diagnostic confirmation, the identification of different types of pathology—is it the amyloid measures that are changing, is it the tau measures that are changing, or is it the neurofilament light that reflects neurodegeneration that's changing? We're going to get so much information. Do they reflect the therapeutic response? When do we remove amyloid? Do we change the blood factors—we're not quite sure of that yet. Could we decide when to stop treatment, or could we decide when to restart treatment if it has been stopped? These are all just great questions, and I think they're going to be driven much more by the biomarkers than they are by our clinical assessments. These blood tests are just going to be a wonderful assistance to physicians.

Transcript edited for clarity. For more coverage of AAIC 2021, 

REFERENCE
Cummings JL, Aisen P, Apostolova LG, Atri A, Salloway S, Weiner M. Aducanumab: Appropriate Use Recommendations. 

Published online July 20, 2021. doi: 10.14283/jpad.2021.41.

Articles

Cummings and colleagues presented appropriate use criteria for the newly approved Biogen/Eisai agent at the 2021 Alzheimer’s Association International Conference.

Jeffrey Cummings, MD, ScD, on Appropriate Use Criteria for Aducanumab

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The Mind Moments podcast features exclusive interviews with leaders in the field discussing the latest research and disease management strategies across the breadth of neurology, including epilepsy, multiple sclerosis, Parkinson disease, dementia, sleep disorders, and more.

Episode 43, "Is Telehealth Here to Stay for Alzheimer Disease Care?" features an exclusive interview with Jessica Zwerling, MD, MS, director, Montefiore Hudson Valley Center of Excellence for Alzheimer’s Disease, and associate professor of neurology, Albert Einstein College of Medicine. She shared her experience with telemedicine in this population over the last year and discussed how it and similar tools can increase access, help overcome social determinants of health, and encourage engagement with the community.

The stories feature in this week's Neurology News Minute, which will give you quick updates on the following developments in neurology, are further detailed here:

's coverage of the 2021 Alzheimer's Association International Conference

Episode Breakdown

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Podcasts

"Mind Moments," a podcast from NeurologyLive, brings you an exclusive interview with Jessica Zwerling, MD, MS.

Episode 43: Is Telehealth Here to Stay for Alzheimer Disease Care?

Institutional Perspectives in Neurology: Multiple Sclerosis

 program, several presentations were given by staff at Mayo Clinic addressed some hot topics in the clinical care and diagnosis of multiple sclerosis (MS), including the latest in therapeutic advances and the many mimics and demyelinating disorders that present similarly to MS, among other topics.

The sessions were moderated by program chair Brian G. Weinshenker, MD, FRCPC, professor of neurology, College of Medicine, Mayo Clinic Rochester. One of the main focuses of the program was new therapies, particularly the landscape of newly approved sphingosine phosphate 1 (S1P) targeting oral medications for MS.

That presentation was given by Jessica L. Stulc, MD, MPH, director, Multiple Sclerosis Treatment and Research Center, Minneapolis Clinic of Neurology, who shared insight specifically into the currently approved therapies for relapsing-remitting MS and the mechanism of action for the new entries in the S1P class, ozanimod (Zeposia; BMS) and ponesimod (Ponvory; Janssen), which were approved in March 2020 and March 2021, respectively. She began by detailing the expression and background on the receptor.

“These are G protein couple receptors that work as a signaling molecule. Primarily, for MS, the function we’re aware of is that it keeps the lymphocytes in the lymph nodes—you have to have signaling to allow egress of the lymphocytes out into the peripheral tissues,” Stulc explained. She also clarified the 5 subtypes of S1P receptors: S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5, the last of which is expressed in the white matter of the central nervous system (CNS).

Ongoing Research in MS Differentiation: Oliver Tobin, MBBCh, BAO, PhD

Stulc then continued by highlighting the major differences between these 2 new additions to the MS therapeutic arsenal. Ozanimod, on the one hand, is selective in its targeting of S1PR1 and S1PR5, and has an active metabolite. It was compared to intramuscular interferon ß1a in both its phase 3 clinical trials, Radiance and Sunbeam. On the other hand, ponesimod is selective in its targeting of only the S1PR1 receptor and has no active metabolite. In its clinical development in the OPTIMUM study, it was compared to teriflunomide (Aubagio; Sanofi). Additionally, it is considered a rapid-acting agent.

Stulc noted that there is a titration for the drug, taking place over 8 days, and for a 0.92-mg maintenance dose. With regard for safety outcomes with ozanimod, in clinical trials, patients treated with the therapy expressed minor heart rate reductions—with an average mean decrease of 1.0-1.2 beats per minute in hour 5 of day 1 of dosing. The maximal effect, she noted, occurred on day 8. Additionally, an average of 1-2 mm Hg decrease in blood pressure was observed related to the safety outcome of hypertension.

In highlighting the prescribing information for the agent, Stulc pointed to the contraindications, specifically that patients with severe and untreated obstructive sleep apnea and those concomitantly using a monoamine oxidase inhibitor. “That is because of the active metabolite, [so there are] the recommended prebaseline assessments. Basically, getting your updated labs, your EKG, et cetera. If there’s a question about other drugs that reduce heartrate, they do recommend a cardiology consult. Only OCT is recommended for those with a history of diabetes or uveitis,” she explained.

For ponesimod, Stulc explained that the safety outcomes in OPTIMUM, there was a similar reduction in heart rate observed, with a mean decrease of 1.0-6.0 beats per minute on day 1, and an atrioventricular (AV) conduction delay—specifically resulting in first-degree AV block in 3.4% of ponesimod patients compared to 1.2% with teriflunomide. No second- or third-degree blocks were observed.

Additionally, she noted that ponsimod is contraindicated for individuals with a myocardial infarction (MI) within the last 6 months, unstable angina, stroke, transient ischemic attack, decompensated heart failure, or class III/IV heart failure. Additionally, a first-dose observation is recommended for all patients with sinus bradycardia, first- or second-degree AV block, or any history of heart failure or MI. Caution is advised, Stulc explained, when patients have severe respiratory disease.

“In terms of clinical considerations, the sequencing of the drug, the timing, the mechanism of action, and then underlying health conditions and medications your patients might be taking [should be top of mind] as you’re considering these medications,” Stulc concluded.

Other presentations at the meeting included the following:

Atypical Forms and Presentations of Demyelinating Disease – W. Oliver Tobin, MBBCh, BAO, PhD

Recently FDA Approved Injectable (B-cell depleting) Medications for MS – Orhun H. Kantarci, MD

Infections on MS Disease Modifying Treatments – Brian G. Weinshenker, MD, FRCPC

For more coverage of Institutional Perspectives in Neurology: Multiple Sclerosis, 

Jessica L. Stulc, MD, MPH, offered an in-depth review of the latest approved therapies in the sphingosine phosphate 1 targeting class of oral medications for MS including ozanimod (Zeposia; BMS) and ponesimod (Ponvory; Janssen).

Cutting Edge Care in Multiple Sclerosis: Advances in S1P Therapy

Pooled data from the phase 3 EMERGE (NCT02484547) and ENGAGE (NCT02477800) clinical trials of aducanumab (Aduhelm; Biogen) suggest that incidences of amyloid-related imaging abnormalities (ARIA) are mostly asymptomatic and that the current literature support routine brain MRI as an effective way to monitor for events in clinical practice.

In total, 454 of the 1105 patients treated with high-dose aducanumab in the 2 trials experienced ARIA. Of those, 76% of patients (n = 344) were asymptomatic while 24% (n = 110) reported symptoms—the majority of which were mild (65%; n = 72) or moderate (16%) in nature. In total, 5 patients (4%) experienced severe symptoms. In comparison, the placebo groups (n = 1087) reported 111 individuals with ARIA, of which 95% (n = 106) were asymptomatic and 5% (n = 5) were symptomatic (mild or moderate, n = 4 [80%]).

ARIA management has been an ongoing area of discussion regarding aducanumab, which was 

approved by the FDA for the treatment of Alzheimer disease

 in June 2021. These data were presented by Patrick Burkett, MD, PhD, medical director, Global Safety, Biogen, at the 2021 

Alzheimer’s Association International Conference (AAIC)

Although ARIA-edema (ARIA-E) was the most common form of the adverse event (AE) reported, with 35% of patients (n = 387) in the treatment groups and 3% (n = 29) of the placebo groups experiencing it, stabilization of ARIA-hemorrhage (ARIA-H) was required for 28% (n = 312) of the treatment and 9% (n = 94) of the placebo groups. Of the total 406 individual cases of ARIA-H, microhemorrhage occurred in 68% (n = 212) of the treatment-group instances and 75% (n = 71) of the placebo-group instances, while superficial siderosis occurred in 51% (n = 162) and 25% (n = 24) of cases, respectively.

“ARIA-E events were typically seen early in treatment, with 50% occurring prior the seventh dose and 90% occurring before the twelfth dose,” Burkett said in his poster presentation. The seventh and twelfth doses were administered at weeks 24 and 44, respectively. All told, 42% (n = 315) of the 749 patients with an 

 gene experienced ARIA-E compared to 20% (n = 72) of those without the gene (n = 356).

The most frequently reported symptom of ARIA was headache (13% of participants with ARIA), while other frequent symptoms included confusion (5%), dizziness (4%), visual disturbance (2%), and nausea (2%).

Biogen Head Pens Open Letter Regarding Aducanumab Controversy in Alzheimer

“ARIA events were assessed both radiographically and clinically, and the combination of these clinical and radiographic criteria impacted the management of those events,” Burkett explained. “Most ARIA events, 98%, resolved radiographically during the course of the clinical studies, typically between 12 and 28 weeks after initial detection. The radiographic severity of ARIA was poorly predictive of the symptomatic status of the events. Radiographic events of ARIA-H were typically seen on the same MRI or follow-up for MRI done to monitor ARIA-E events.”

He and colleagues noted in their poster that the study protocol following ARIA-E was to suspend dosing when patients were symptomatic at all, or if they were asymptomatic, to continue dosing unless ARIA-E reached a moderate or severe nature. For ARIA-H, the plan was similar, though when reaching a severe nature, dosing would be discontinued. Serious cases of both ARIA-E and ARIA-H—symptomatic or otherwise—were to result in automatic discontinuation.

Of those who experienced ARIA-E and received at least 1 more dose of aducanumab (n = 172), 58% (n = 100) of cases remained mild and asymptomatic, while 42% (n = 72) experienced change. Of those, notably, new-onset symptoms were reported in roughly 6% (n = 11) of cases, while 40% (n = 69) developed into either moderate (99%) or severe (1%) ARIA cases on MRI.

REFERENCE
Burkett P, Chalkias S, Umans K, et al. Considerations for the Real-World Management of ARIA From the Aducanumab Phase 3 Studies EMERGE and ENGAGE. Presented at: AAIC 2021; Denver, Colorado; July 26-30, 2021. Poster 57498.

Pooled data from the phase 3 clinical development of aducanumab (Aduhelm; Biogen) suggest that ARIA remains a mostly asymptomatic problem, with MRI providing an effective way to monitor events.

Matt Hoffman

Articles

Jeffrey Cummings, MD, ScD, on Appropriate Use Criteria for Aducanumab

Episode 43: Is Telehealth Here to Stay for Alzheimer Disease Care?

Cutting Edge Care in Multiple Sclerosis: Advances in S1P Therapy

ARIA Events Most Often Asymptomatic in Aducanumab Treatment